Immunologic regulation by theta defensins

Abstract

The invention provides a method of inhibiting undesirable microbial contamination, invasion, or growth in an individual by administering to the individual an effective amount of a theta defensin. The invention additionally provides a method of inhibiting deleterious effects resulting from microbial contamination, invasion, or growth in an individual by administering to an individual an effective amount of a theta defensin, whereby immune-mediated pathology is limited and immune function is improved.

1 . A method of inhibiting undesirable microbial growth in an individual comprising administering to said individual an effective amount of a theta defensin, whereby microbial growth is inhibited. 
     
     
         2 . The method of  claim 1 , wherein said undesirable microbial growth is an infection. 
     
     
         3 . The method of  claim 1 , wherein said undesirable microbial growth is polymicrobial. 
     
     
         4 . The method of  claim 1 , wherein said undesirable microbial growth results in systematic inflammatory response syndrome, sepsis, septic shock, or immunoparalysis. 
     
     
         5 . A method of inhibiting an effect of microbial growth in an individual comprising administering to said individual an effective amount of a theta defensin, whereby microbial growth is inhibited. 
     
     
         6 . The method of  claim 5 , wherein said effect is an inflammatory response. 
     
     
         7 . The method of  claim 5 , wherein said effect is an immunosuppressed state. 
     
     
         8 . The method of  claim 5 , wherein said effect is an autoimmune disease. 
     
     
         9 . The methods of  claim 1 , wherein said theta defensin is selected from a peptide selected from the peptides set forth in  FIG. 1 . 
     
     
         10 . The method of  claim 1 , wherein said theta defensin is a cationic, arginine-rich cyclic peptide having each amino acid linked by a peptide bond and having one or more intrachain crosslinks, said intrachain crosslink formed between two amino acids, said theta defensin peptide or functional fragment lacks a free amino or carboxyl terminus, has less than 29 amino acids, and possesses antimicrobial activity. 
     
     
         11 . The method of  claim 1 , wherein said theta defensin is a cationic, arginine-rich cyclic peptide having each amino acid linked by a peptide bond and having one or more intrachain crosslinks, said intrachain crosslink formed between two amino acids, said theta defensin peptide or functional fragment lacks a free amino or carboxyl terminus, has less than 29 amino acids, and improves the immune function of the individual. 
     
     
         12 . The method of  claim 1 , wherein said theta defensin peptide has the amino acid sequence:
 Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa1-Xaa6-Xaa4-Xaa4-Xaa1-Xaa1-Xaa6-Xaa4-Xaa5-Xaa1-Xaa3-Xaa7-Xaa8,   wherein
 Xaa1 independently is an aliphatic amino acid; 
 Xaa2 is an aromatic amino acid; 
 Xaa3 is Cys or Trp; 
 Xaa4 independently is Arg or Lys; 
 Xaa5 is Cys or Trp; 
 Xaa6 is Cys or Trp; 
 Xaa7 is Thr or Ser; and 
 Xaa8 is Arg or Lys. 
   
     
     
         13 . The method of  claim 1 , wherein said theta defensin peptide has the amino acid sequence:
 Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa1-Xaa6-Xaa4-Xaa4-Xaa1-Xaa1-Xaa6-Xaa4-Xaa5-Xaa1-Xaa3-Xaa7-Xaa8,   wherein
 Xaa1 independently is Gly, Ile, Leu, Val or Ala; 
 Xaa2 is Phe, Trp or Tyr; 
 Xaa3 is Cys or Trp; 
 Xaa4 independently is Arg or Lys; 
 Xaa5 is Cys or Trp; 
 Xaa6 is Cys or Trp; 
 Xaa7 is Thr or Ser; and 
 Xaa8 is Arg or Lys. 
   
     
     
         14 . The method of  claim 13 , wherein said theta defensin has the amino acid sequence:
 Gly-Phe-Cys-Arg-Cys-Leu-Cys-Arg-Arg-Gly-Val-Cys-Arg-Cys-Ile-Cys-Thr-Arg (SEQ ID NO:).   
     
     
         15 . The method of  claim 13 , wherein Xaa1 is linked through a peptide bond to Xaa8. 
     
     
         16 . The method of  claim 13 , wherein an intrachain crosslink is formed between two amino acids selected from the group consisting of:
 Xaa3 at position 3 and Xaa3 at position 16;   Xaa5 at position 5 and Xaa5 at position 14; and   Xaa6 at position 7 and Xaa6 at positionl2.   
     
     
         17 . The method of  claim 16  wherein Xaa1 is linked through a peptide bond to Xaa8. 
     
     
         18 . The method of  claim 16 , wherein said intrachain crosslink is a disulfide crosslink. 
     
     
         19 . The method of  claim 16 , wherein said intrachain crosslink is a di-tryptophan crosslink. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 17 , having the amino acid sequence:
 Gly-Phe-Cys-Arg-Cys-Leu-Cys-Arg-Arg-Gly-Val-Cys-Arg-Cys-Ile-Cys-Thr-Arg (SEQ ID NO:).   
     
     
         22 - 60 . (canceled)